Molecular insights into the problem of pain

Stephen P. Hunt, PhD. FMedSci. Professor of Molecular Neuroscience. Department of Anatomy and Developmental Biology. Medawar Building. University College London. Gower Street. London WC1E 6BT. U.K.

Our understanding how the brain acquires and processes visual, auditory, taste, olfactory and somatosensory information has undergone a revolution in the past two decades. Probably in no other sensory modality has more rapid and profound progress been made than in our understanding of the mechanisms by which information is transmitted and processed in both the normal and pathological state. Remarkable strides have been made in understanding the cellular and molecular basis of how pain is transmitted and modulated. This rapid progress is due in large part to the multidisciplinary approach that has been taken that simultaneously employs systems neurobiology, behavioral analysis, genetics and cell and molecular techniques. In addition to the rapid advances in understanding the mechanisms by which pain is transmitted from peripheral tissues to the central nervous system, these advances have also provided novel targets for treating pathological chronic pain that is now recognized as a disease entity in its own right.

Nociceptive information reaches the brain from the peripheral site of injury through multiple parallel neuronal pathways. At every stage of the pain pathway, from sensory receptor to spinal cord, from cord to brain stem and from brain stem to the cerebral cortex, information signalling injury is subdivided or shared amongst these parallel systems. Molecular dissection of these different pathways has begun to reveal functions for these separate pathways and their contribution to the final behavioural outcome. Each neuron in the ascending nociceptive pathway has the capacity to change phenotype in the face of a sustained peripheral injury and there is growing evidence to indicate that the role of particular neuronal subsystems in nociception may only become apparent during the process of injury and repair. Different patterns of phenotypic changes characterise different pain conditions and it is these different molecular signatures that will finally need to be considered if effective pain control is to be achieved. Pain is usually thought to be "acute" or "chronic" depending on the duration of the pain condition and "neuropathic" when pain derives from direct damage to the nervous system. These different pain states generally require different types of pharmacological intervention to suppress the pain but in some cases remain resistant to any sort of drug treatment. The challenge for molecular neurobiology is as much to uncover new targets for analgesic drugs as to understand the principles by which nociceptive information is transformed in the behaving animal. Considerable progress has been made. Much of it has been dependent on the selective deletion of particular genes in mice using homologous recombination or by the selective ablation of discrete biochemically defined neuronal populations.

I will highlight a number of recent advances that will impact upon our understanding of the generation and control of chronic pain in man. I will describe the sensory pathways that have been identified as crucial in modulating the sensitivity to pain and which may undergo long-term plastic changes that lead to the development of chronic pain states. For example, molecular analysis has identified the small diameter sensory C fibres as important. Selectively knocking out the gene coding for the capsaicin receptor which is expressed exclusively by C fibres has only minor effects on thermal nociception but prevents the development of hyperalgesia following inflammation (Caterina et al 2000 : Davis et al.. 2000).

It has been found that those neurons in the superficial spinal cord that express the substance P (NK1) receptor, receive a massive input from substance P releasing sensory fibres and project upon the brain stem. can be specifically ablated with a substance P-saporin conjugate. This results in a substantially reduced hyperalgesia and allodynia following the establishment of a variety of inflammatory pain states. The success of this approach led to the second study in which it was shown that SAP-SP ablation would reverse the effects of a previous established neuropathic or inflammatory pain state. The clinical possibilities of this approach are enormous (Nichols et al 1999).

We recently described a novel phenotype of the NK1 knockout mouse. There are an enormous number of changes in the behavioural response of these animals particularly to stress and danger in the environment. For example, the mice show a loss of stress-induced analgesia and reduced aggression but normal responses to thermal and mechanical noxious stimuli (De Felipe et al., 1998). What has proved most unexpected has been the finding that knockout of this gene allows us to dissociate the analgesic from the rewarding properties of opiates (Murtra et al.. 2000). Thus NK1 knockout animals no longer reward to morphine but pain control is largely intact. This may have major implications for the prescribing of opiates for chronic pain conditions given the concern that many clinicians have for inducing dependant and addictive states in their patients.

Finally. I will highlight a recent and remarkable success in the control of bone cancer pain in a mouse model using a decoy receptor, osteoprotegcrin which halts the excessive tumour-induced bone destruction that is involved in the generation of bone cancer pain (Honore et al, 2000). Given the prevalence of bone cancer pain in the population, any treatment that results in substantial pain relief in this population of patients must be regarded as a major breakthrough.


Hunore P, Luger MM, Sabino MA. Schwci MJ, Rogers SD. Mach DB. O'keefe PF. Ramnaraine ML. Clohisy DR. Mantyh PW. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med. (2000) ,6:521-8.

Nichols ML, Alien BJ, Rogers SD. Ghilardi JR. Honore P, Luger NM, Finke MP. Li J. Lappi DA. Simone DA. Mantyh PW. Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science (1999) : 286 : 1558-61.
Murtra P, Sheasby AM. Hunt SP. De Felipe C. Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature (2000) :405 : 180-3.

De Felipe C. Hen-ero JF, O'Brien JA. Palmer JA. Doyle CA. Smith AJ, Laird JM. Belmonte C. Cervero F. Hunt SP. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature. (1998) : 392 : 394-7.

Caterina M J. Leffler A, Malmberg AB. Martin WJ, Trafton J. Petersen-Zeitz KR. Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. (2000) ; 283 : 306-13.

Davis JB. Gray J, Gunthorpe MJ. Hatcher JP, Davey PT. Overend P. Harries MH, Latcham J. Clapham C, Atkinson K, Hughes SA, Ranee K, Grau E. Harper AJ. Pugh PL, Rogers DC. Bingham S. Randall A, Sheardown SA. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.Nature. 2000 : 405 : 183-7.

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 53 - 54.