As it is well known opioids are the most powerful drugs used for acute and chronic pain, although, their several serious side effects, such as respiratory depression, mental clouding, constipation, and tolerance dependence producing capacity, as well as large interpatient variability in responses limit their safe everyday use. Furthermore, the treatment of certain types of pain (e.g. neuropathic pain) is not very satisfactorily managed. Consequently, there is a continuous need to find analgesics efficient against chronic neuropathic pain and avoid these side actions and still retain opioid like potency. There are several possible way to find new targets for these purposes. Recently opioid receptors have been identified on peripheral processes of sensory neurons. These findings provide new insights into intrinsic mechanisms of pain control and suggest innovative strategies for developing drugs and alternative approaches to pain treatment. In the effort to discover better analgesic drugs for chronic pain, attention is being paid to specific ion channels at the periphery, include members of transient receptor potential family (TRPV1, capsaicin receptors), as well as P2x receptors, sensitive to purines released from tissue injury. A special tetradotoxin-resistant, voltage dependent type of sodium channel is associated with dorsal root ganglia neurons is blocked by mexiletine, used in chronic pain. A synthetic peptide analogue of marine snail toxin ziconitine blocks N-type calcium channels. GABA and NMDA receptors are also involved in the antinociceptive actions of gabapentin and ketamine, respectively. Furthermore nicotine and analogues (epibatidine) induce analgesia through nicotinic ACh receptors. We studied mostly the peripheral targets of hydrophilic heterocyclic opioids in antinociceptive processes.